Over 47% of American adults aged 30 and over have periodontitis. Further, periodontitis is twice as prevalent in diabetics as in non-diabetics, and type 2 diabetes (T2D) currently afflicts 40 million Americans. T2D-associated periodontitis is severe and, in many cases, refractory to current treatments due to the altered and aberrant functions of bone cells in hyperglycemic conditions. Therefore, developing an effective method to restore and regenerate lost alveolar bone to reserve the natural teeth in diabetics is critically important. Adiponectin, an adipokine, has anti-inflammatory and anti-diabetic properties. We have found that adiponectin inhibits differentiation and activity of osteoclasts and significantly decreases alveolar bone loss. At the same time, it promotes the osteoblast niche and mesenchymal stem cell migration, and enhances bone defect healing. However, adiponectin protein-based therapy has disadvantages that limit its clinical application, including adverse immunoreactions and the need for constant IV injection of high doses for therapeutic effect. An adiponectin receptor agonist, AdipoRon (APR) was recently identified (Nature 503:493-9, 2013), which can be orally administrated to ameliorate insulin resistance and glucose intolerance, and prolong the shortened lifespan of diabetic mice. Our preliminary studies indicate that APR upregulates expression and activity of adiponectin receptors exerting favorable effects on bone cell metabolism. Our purpose is to use APR, a small molecule chemical compound, as a novel therapeutic agent to effectively treat diabetic periodontitis. Our central hypothesis is that, in addition to systemically controlling hyperglycemia and inflammation, APR directly triggers molecular signals that correct the imbalance of bone resorption and formation, reversing pathology and promoting regeneration of lost alveolar bone, and allowing the natural teeth to be reserved. In Aim 1 we will first determine the affinity and efficacy of APR binding to adiponectin receptors in bone cells, initiation of downstream signal mediator expression, and enhancement of bone formation. To verify the specificity and affinity of the interaction between this novel exogenous agonist and endogenous receptor, we will use receptor knock out mice. In Aim 2 we will delineate the APR effect in ameliorating and correcting diabetic 'mobilopathy' - in which cell differentiation, recruitment and migration are seriously impaired in diabetes. We will use an adiponectin knock out mouse line to determine if APR can effectively surrogate adiponectin in promoting the necessary microenvironment and deploying sufficient bone forming cells to regenerate alveolar bone damaged in periodontitis. In Aim 3 we will generate experimental periodontitis in a mouse model of diabetes to further determine the overall effects of APR in reducing hyperglycemia and inflammation as well as its anabolic effect for periodontal bone regeneration. This translational research will yield initial characterization of a novel therapeutic agent with strong potential for treating diabetic periodontal disease and provide baseline information for drug development for treating periodontitis and other bone diseases associated with diabetes.